Injectable collagen crosslink augmentation for degenerative disc disease

描述（由申请人提供）：关于腰痛的患病率和社会成本，很少有同行。由于患者人数每年超过1500万，估计每年的社会成本在1000亿美元左右。目前对这种疾病的治疗方案，包括物理治疗、药物治疗和手术治疗，收效有限。该方案涉及一种新颖的、非手术的、经济有效的组织再生方法，有望用于治疗机械和营养不良的组织，如椎间盘。先前的体外和体内研究已经证明了可注射胶原交联增强剂在稳定脊柱关节、减少负载下的椎间盘突出、增加组织的强度、抗撕裂性和耐久性方面的功效，同时也改善了这些主要无血管组织的营养流动。I期试验通过机械、热和蛋白酶消化试验成功地表征了7种候选药物在椎间盘环纤维化（AF）组织中的交联效应。确定了至少一种优选剂，并对浓度、pH、调理和缓冲进行了优化，以最大限度地提高交联效率和机械效果。最近，已经进行了体外测定，以确定制剂和缓冲液的生物相容性。拟议的II期试验将为监管申报和首次人体临床试验提供必要的数据。试剂输送、渗透、反应动力学、持久性（效果持续时间）和储存要求（保质期）将被彻底调查。将在动物模型中进行急性、功能性生物相容性和神经毒性研究，以量化预期和最坏情况下的治疗效果。交联效应的进一步表征将使用人类AF组织的不同亚群（年龄、组成、变性的变化）来确定。通过将这种突破性的治疗方法带到临床试验的门槛，SBIR的资金将在提供一种新颖的、具有成本效益的治疗下腰痛和残疾的最终目标方面发挥至关重要的作用。

DESCRIPTION (provided by applicant): With regard to prevalence and cost to society, low-back pain has few peers. With a patient population in excess of 15 million/year, the societal cost is estimated to be in the realm of $100 billion/year. Current treatment options for this disease have shown limited success, including physical therapy, medication and surgery. This proposal involves a novel, nonsurgical and cost-effective, tissue revitalization approach which shows promise for treatment of mechanically and nutritionally challenged tissues like the spinal disc. Previous in vitro and in vivo studies have demonstrated the efficacy of Injectable collagen crosslink augmentation in stabilizing spinal joints, decreasing disc bulge under load, increasing the strength, tear resistance, and durability of the tissue, while also improving nutritional flow to these largely avascular tissues. Phase I testing was successful in characterizing the crosslinking effects of seven candidate agents in disc annulus fibrosis (AF) tissue using mechanical, thermal and protease digestion assays. At least one preferred agent was identified, and concentration, pH, conditioning, and buffering were optimized to maximize the efficiency of crosslinking and mechanical effect. Recently, in vitro assays have been undertaken to determine agent and buffer biocompatibility. The proposed Phase II testing will provide data necessary for regulatory filings and first-in-man clinical trials. Reagent delivery, penetration, reaction kinetics, permanency (effect duration), and storage requirements (shelf life) will be thoroughly investigated. Acute, functional biocompatibility and neurotoxicity studies will be conducted to quantify expected and worst-case treatment effects in an animal model. Further characterization of crosslinking effects will be determined using different subgroups of human AF tissues (variations in age, composition, degeneration). By bringing this path-breaking treatment to the doorstep of clinical trials, SBIR funding will play a vital role in enabling progress towards the ultimate goal of providing a novel, cost-effective treatment in the struggle against low back pain and disability. PUBLIC HEALTH RELEVANCE: Back pain and disability associated with spinal degeneration and instability remains among the most costly and prevalent health problems in the US today. With a patient population in excess of 15 million/year, the societal cost is estimated to be in the realm of $100 billion/year. Due to the limited success of current treatment options, it is reasonable to expect that an effective nonsurgical solution could revolutionize clinical care for this pandemic.